English

• 由于氟原子独特的性质, 含氟有机化合物被广泛应用于医药、农药、功能材料和生命科学等领域^[1].二氟亚甲基的引入可以显著提高分子的代谢稳定性和口服生物利用度, 已成为药物研发的一种重要手段^[2].近年来, 炔烃的二氟烷基化反应引起了化学工作者的广泛关注^[3-12].炔烃的二氟烷基化双官能团化反应在引入二氟烷基的同时, 能够实现其它官能团的引入, 具有良好的步骤经济性和产物结构多样性, 可以快速构建官能团化的氟烷基取代烯烃化合物库, 因而得到了快速发展^[4-12].例如, 胡金波等^[8]采用Et₃B为自由基引发剂, 实现了非活化末端炔烃的碘-二氟烷基化反应(Scheme 1a).采用铁或铂光催化剂, Hu^[9]和支志明^[10]等分别发展了末端炔烃的反式-碘-二氟烷基化反应.王细胜等^[11]通过铜催化的自由基加成/脱羧串联反应, 实现了丙炔酸衍生物的碘-二氟烷基化反应.以CoBr₂为催化剂, von Wangelin等^[12]发展了芳基炔烃的反式-溴-二氟烷基化反应, 进一步拓展了卤-二氟烷基化的适用范围.

  图式 1

  

  图式 1.  炔烃的卤-氟烷基化反应

  Scheme 1.  Halo-fluoroalkylation of alkynes

  下载: 全尺寸图片 幻灯片

  尽管炔烃的卤-烷基化反应取得了较快发展^[8-12], 但仍然存在一些有待解决的问题.首先, 传统方法通常是末端炔烃的转化, 活性相对较低的非末端炔烃的反应较为少见.其次, 反应的选择性例如区域和立体选择性有待提高.更重要的是, 以往的反应属于1, 2-双官能团化, 而炔烃的远程卤-烷基化反应还未见报道.最近, 我们通过杂原子控制碳-碳叁键氟烷基化的区域选择性, 相继实现了杂原子取代炔烃的远程氧化-氟烷基化^[13]和炔基化-三氟甲基化反应^[14], 为远端官能团化氟烷基取代烯烃的合成提供了高效、高选择性的方法.在以上工作基础上, 本工作发展了一个可见光催化^[15]的炔硫醚远程卤-二氟烷基化反应(Scheme 1b), 一步合成了远端卤代的(Z)-氟烷基取代烯烃, 反应的区域、立体和位点选择性优秀, 为含氟功能分子的精准合成提供了有效途径.需要指出的是, 该反应实现了远程碳-氢键的卤代^[16], 包括溴代、碘代和氯代, 为惰性碳-氢键的直接卤代提供了新思路.

  1.   结果与讨论

  首先, 选取炔硫醚^[17]1a对反应条件进行了优化.采用BrCF₂CO₂Et (2a, 2.0 equiv.)为氟烷基自由基源, fac - Ir(ppy)₃ (2 mol%)为光催化剂, 2, 6-二甲基吡啶(2.0 equiv.)为添加剂, 15 W蓝色LED灯为光源, 溴乙烷为溶剂, 室温反应36 h, 以72%的产率得到远程溴-二氟烷基产物3aa(表 1, Entry 1).采用Ru(bpy)₃Cl₂为光催化剂则导致反应效率和选择性明显下降(Entry 2).接下来, 以fac -Ir(ppy)₃为光催化剂, 对反应添加剂进行了优化.结果发现, 吡啶、2, 4, 6-三甲基吡啶、醋酸钾、碳酸钾和磷酸氢二钾等都不如2, 6-二甲基吡啶(Entries 3~8).采用MeCN、二甲基亚砜(DMSO)或二氯甲烷(DCM)为溶剂, 3aa的产率变化不大, 但是, 氢二氟烷基化副产物3aa'开始增多(Entries 9~11).控制实验表明, 无论2, 6-二甲基吡啶还是fac -Ir(ppy)₃, 对该反应都起着重要作用(Entries 13, 14).

  表 1

  

  表 1  炔硫醚远程溴-二氟烷基化反应条件优化^a

  Table 1.  Optimization of reaction conditions for the remote hlao-difluoroalkylation of thioalkynes

  下载: 导出CSV

  Entry	Deviations from standard condition	Yieldb /% of 3aa/3aa'
  1	None	72/＜5
  2	Ru(bpy)3Cl2 instead of fac -Ir(ppy)3	25/5
  3	Et3N instead of 2, 6-lutidine	65/9
  4	Pyridine instead of 2, 6-lutidine	61/7
  5	2, 4, 6-collidine instead of 2, 6-lutidine	55/4
  6	KOAc instead of 2, 6-lutidine	70/8
  7	K2CO3 instead of 2, 6-lutidine	62/4
  8	K2HPO4 instead of 2, 6-lutidine	68/6
  9	MeCN instead of EtBr	69/10
  10	DMSO instead of EtBr	70/7
  11	DCM instead of EtBr	69/15
  12	THF instead of EtBr	7/2
  13	Without 2, 6-lutidine	9/4
  14	Without fac -Ir(ppy)3	NR
  a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), fac -Ir(ppy)3 (2 mol%), 2, 6-lutidine (0.4 mmol), EtBr (2 mL), 25 ℃, 15 W blue LEDs, 36 h. b Isolated yield. NR＝No reaction.

  在实现优化反应条件之后, 对杂原子取代炔烃的底物适用范围进行了研究(表 2).首先, 考察了硫取代基对反应的影响.无论芳基炔硫醚还是脂肪基炔硫醚, 反应都能很好地进行, 以良好的产率得到远程溴-二氟烷基化产物(3aa~3ea), 反应的区域、立体和位点选择性优秀.延长远端碳链的长度, 依然可以得到很好的收率(3fa, 3ga).接下来, 考察了反应的官能团兼容性.结果发现, 醚(OTBS, OMe)、酯基(OAc)、卤原子(Br, Cl)和酰胺(NPhth)都能很好地兼容(3ha~3ma), 这些基团为产物的进一步衍生化提供了可能.炔丙位及高炔丙位取代基的引入不会影响反应的进行(3na, 3oa).除了二级碳-氢键直接溴化之外, 三级碳-氢键也能顺利转化, 得到相应的溴代产物3pa, 不过反应伴随着少量氢二氟烷基化产物3pa'和消除产物3pa" 的生成.此外, 苄位碳-氢键的溴代反应也能顺利进行(3ra).该远程溴-二氟烷基化反应可以拓展到炔基硒化合物, 而炔醚在该反应条件下则基本不反应(3ta, 3ua).

  表 2

  

  表 2  杂原子取代炔烃的底物范围^a

  Table 2.  Substrate scope of heteroalkynes

  下载: 导出CSV

  a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), fac -Ir(ppy)3 (2 mol%), 2, 6-lutidine (0.4 mmol), EtBr, blue LEDs, 25 ℃, 36 h; isolated yields are given. b dr ＝1.8:1. c dr ＝1.5:1. d Determined by GC-MS. e Similar with the reaction of 1p, 11% yield of hydrodifluoroalkylation product 3ra' and＜5% yield of remote desaturated product 3ra'' was observed by GC-MS. f 14% yield of hydrodifluoroalkylation product 3sa' was observed by GC-MS.

  接下来, 以1a为偶联试剂, 对自由基前体进行了研究(表 3).令人高兴的是, 各种溴代二氟乙酰胺都能顺利反应, 以中等到良好的产率得到远程溴-二氟烷基化产物(3ab~3af), 反应的区域、立体和位点选择性优秀.以Umemoto试剂为三氟甲基源, NaBr或NaI为卤离子源, 分别实现了炔硫醚的远程溴-三氟甲基或碘-三氟甲基化反应(3ah, 3ai)(产率未进一步优化), 该结果说明反应可能经历碳正离子中间体.令人高兴的是, 其它自由基前体也能参与该反应.例如, 对甲基苯磺酰氯(TsCl)为偶联试剂, 以57%的产率得到了远程氯-磺化产物(3aj).

  表 3

  

  表 3  自由基前体范围^a

  Table 3.  Scope of radical precursors

  下载: 导出CSV

  a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), fac -Ir(ppy)3 (2 mol%), 2, 6-lutidine (0.4 mmol), EtBr, blue LEDs, 25 ℃, 36 h; isolated yields are given. b Umemoto’s reagent (0.4 mmol), NaX (0.6 mmol), and ClCH2CH2Cl were used instead of 2a and EtBr.

  然后, 对该反应机理进行了研究.在标准反应条件下, 加入2.0 equiv.的自由基捕获试剂四甲基哌啶氧化物(TEMPO), 反应被完全抑制, 并观察到了4a^[18]的生成(Scheme 2), 说明反应可能经历二氟烷基自由基中间体.在反应体系加入2.0 equiv. MeOH, 高分辨质谱检测到了远程碳-氢键甲氧基化产物4b, 再次说明反应可能经历碳正离子中间体.开关灯实验表明(图 1), 光照对反应的进行是必须的.

  图式 2

  

  图式 2.  机理研究

  Scheme 2.  Mechanistic studies

  下载: 全尺寸图片 幻灯片

  图 1

  

  图 1.  化合物1a和2a反应的开关灯实验

  Figure 1.  Light on/off experiment of the reaction between 1a and 2a

  下载: 全尺寸图片 幻灯片

  根据上述实验结果和我们之前的工作^[13-14], 可能的反应机理如Scheme 3所示.首先, fac -Ir(ppy)₃经可见光照射转化为激发态的*Ir(III), 接着, 它与R_fX单电子转移(SET)产生氟烷基自由基R_f•^[19].硫原子对碳-碳叁键的给电子共轭效应将使得电子密度较高的β -炔碳原子选择性与亲电氟烷基自由基结合, 生成烯基自由基I; 当然, 硫原子的孤对电子对邻位烯基自由基的共轭作用也会有利于I的生成.随后, 烯基自由基分子内1, 5-氢原子迁移(1, 5-HAT)^[20]、SET氧化生成碳正离子III, 最后, 卤离子进攻碳正离子得到相应的远程卤-氟烷基化产物, 同时再生光催化剂Ir(III).

  图式 3

  

  图式 3.  可能的反应机理

  Scheme 3.  Possible reaction mechanism

  下载: 全尺寸图片 幻灯片

  2.   结论

  发展了一个可见光催化的炔硫醚远程卤-二氟烷基化反应, 一步合成了远端卤代的(Z)-二氟烷基取代的烯基硫醚, 产率中等到良好, 反应的区域、立体和位点选择性优秀.反应一步构建了3根新的化学键, 实现了惰性碳-氢键的直接卤代, 包括溴代、碘代和氯代, 同时构建了热力学相对不稳定的(Z)-烯烃, 为复杂分子的精准合成提供了温和高效的方法.

  3.   实验部分

  3.1   仪器与试剂

  ¹H NMR、¹³C NMR和¹⁹F NMR谱采用德国布鲁克公司600或400 MHz核磁共振仪进行测定.高分辨质谱采用布鲁克公司MicroTof-Q II液质联用高分辨质谱仪测定, 离子源为ESI-TOF.用硅胶(200~300目)进行柱层析分离.除非另有说明, 所有试剂和溶剂均购自商业供应商, 未经进一步纯化.

  3.2   实验方法

  在干燥的15 mL反应管中, 氮气保护下加入fac - Ir(ppy)₃ (2.6 mg, 0.004 mmol), 1 (0.2 mmol), 2 (0.4 mmol), 2, 6-二甲基吡啶(42.9 mg, 0.4 mmol)和2 mL干燥的溴乙烷, 距离反应管约5 cm处用15 W蓝色LED灯25 ℃下照射搅拌36 h.待反应结束后, 加入5 mL水淬灭反应, 再用乙酸乙酯(10 mL×4)萃取, 有机相用饱和氯化钠溶液洗涤, 无水硫酸钠干燥, 旋转蒸发除去溶剂.粗产品用200~300目硅胶柱层析[V (乙酸乙酯):V (石油醚)＝1:30]分离, 得到目标产物3.

  3-苯硫基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3aa): 56 mg, 黄色液体, 产率72%. ¹H NMR (600 MHz, CDCl₃) δ : 7.35~7.33 (m, 4H), 7.31~7.28 (m, 1H), 6.61 (s, 1H), 4.33 (q, J ＝7.1 Hz, 2H), 4.20~4.09 (m, 1H), 2.64~2.56 (m, 1H), 2.51~2.39 (m, 1H), 2.05~1.92 (m, 2H), 1.75 (d, J ＝6.7 Hz, 3H), 1.33 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝34.6 Hz), 135.0, 131.3 (t, J ＝5.8 Hz), 130.7 (t, J ＝23.5 Hz), 123.0, 129.3, 127.6, 113.6 (t, J ＝252.1 Hz), 63.2, 50.5, 39.6, 31.4 (t, J ＝3.3 Hz), 26.5, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ :-99.0 (d, J ＝273.1 Hz), -99.6 (d, J ＝273.1 Hz); HRMS (ESI) calcd for C₁₆H₂₀BrF₂O₂S (M+H)⁺ 393.0330, found 393.0323.

  3-对氯苯硫基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3ba): 57 mg, 黄色液体, 产率67%. ¹H NMR (600 MHz, CDCl₃) δ : 7.33~7.31 (m, 2H), 7.29~7.27 (m, 2H), 6.54 (s, 1H), 4.33 (q, J ＝7.2 Hz, 2H), 4.17~4.12 (m, 1H), 2.63~2.59 (m, 1H), 2.49~2.44 (m, 1H), 2.03~1.91 (m, 2H), 1.75 (d, J ＝6.7 Hz, 3H), 1.33 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.3 (t, J ＝34.5 Hz), 133.8, 133.4, 131.5 (t, J ＝23.6 Hz), 131.2, 130.5 (t, J ＝5.7 Hz), 129.4, 113.5 (t, J ＝252.3 Hz), 63.3, 50.4, 39.5, 31.4 (t, J ＝3.5 Hz), 26.5, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -99.0 (d, J ＝273.5 Hz), -99.7 (d, J ＝273.4 Hz); HRMS (ESI) calcd for C₁₆H₁₈BrClF₂O₂SNa (M+Na)⁺ 448.9760, found 448.9758.

  3-对甲氧基苯硫基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3ca): 64 mg, 黄色液体, 产率76%.¹H NMR (400 MHz, CDCl₃) δ : 7.32~7.30 (m, 2H), 6.89~6.86 (m, 2H), 6.51 (s, 1H), 4.36 (q, J ＝7.1 Hz, 2H), 4.17~4.09 (m, 1H), 3.81 (s, 3H), 2.59~2.52 (m, 1H), 2.44~2.37 (m, 1H), 2.03~1.88 (m, 2H), 1.73 (d, J ＝6.7 Hz, 3H), 1.36 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.5 (t, J ＝34.7 Hz), 159.7, 133.4 (t, J ＝5.8 Hz), 132.8, 128.7 (t, J ＝23.6 Hz), 125.4, 114.9, 113.7 (t, J ＝252.0 Hz), 63.1, 55.4, 50.5, 39.7, 31.2 (t, J ＝3.5 Hz), 26.4, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -99.2 (d, J ＝271.8 Hz), -99.8 (d, J ＝271.8 Hz); HRMS (ESI) calcd for C₁₇H₂₁BrF₂O₃SNa (M+Na)⁺ 445.0255, found 445.0262.

  3-乙硫基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3da): 47 mg, 黄色液体, 产率68%.¹H NMR (400 MHz, CDCl₃) δ : 6.40 (s, 1H), 4.34 (q, J ＝7.1 Hz, 2H), 4.17~4.09 (m, 1H), 2.71 (q, J ＝7.4 Hz, 2H), 2.57~2.51 (m, 1H), 2.44~2.36 (m, 1H), 2.02~1.86 (m, 2H), 1.74 (d, J ＝6.7 Hz, 3H), 1.36 (t, J ＝7.1 Hz, 3H), 1.30 (t, J ＝7.4 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.5 (t, J ＝34.9 Hz), 132.9 (t, J ＝6.1 Hz), 127.9 (t, J ＝23.5 Hz), 113.7 (t, J ＝251.6 Hz), 63.0, 50.7, 39.8, 31.4 (t, J ＝3.2 Hz), 29.2, 26.5, 15.3, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -100.2 (d, J ＝269.7 Hz), -100.8 (d, J ＝269.8 Hz); HRMS (ESI) calcd for C₁₂H₁₉- BrF₂O₂SNa (M+Na)⁺ 367.0149, found 367.0152.

  3-甲硫基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3ea): 44 mg, 黄色液体, 产率67%.¹H NMR (600 MHz, CDCl₃) δ : 6.35 (s, 1H), 4.35 (q, J ＝7.1 Hz, 2H), 4.15~4.09 (m, 1H), 2.54~2.49 (m, 1H), 2.40~2.35 (m, 1H), 2.31 (s, 3H), 2.00~1.88 (m, 2H), 1.74 (d, J ＝6.7 Hz, 3H), 1.36 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝35.0 Hz), 134.6 (t, J ＝5.9 Hz), 127.4 (t, J ＝23.6 Hz), 113.8 (t, J ＝252.2 Hz), 63.0, 50.7, 39.8, 31.3 (t, J ＝3.5 Hz), 26.4, 18.4, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -100.8 (d, J ＝4.9 Hz); HRMS (ESI) calcd for C₁₁H₁₇Br- F₂O₂SNa (M+Na)⁺ 352.9993, found 352.9990.

  3-苯硫基亚甲基-2, 2-二氟-6-溴辛酸乙酯(3fa): 65 mg, 黄色液体, 产率80%.¹H NMR (400 MHz, CDCl₃) δ : 7.35~7.31 (m, 4H), 7.31~7.27 (m, 1H), 6.61 (s, 1H), 4.33 (q, J ＝7.1 Hz, 2H), 4.04~3.97 (m, 1H), 2.68~2.61 (m, 1H), 2.52~2.44 (m, 1H), 2.09~1.92 (m, 2H), 1.93~1.84 (m, 2H), 1.33 (t, J ＝7.1 Hz, 3H), 1.06 (t, J ＝7.3 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝34.7 Hz), 135.0, 131.2 (t, J ＝5.9 Hz), 130.8 (t, J ＝23.5 Hz), 129.9, 129.3, 127.5, 113.6 (t, J ＝251.9 Hz), 63.2, 59.0, 37.3, 32.2, 31.2 (t, J ＝3.3 Hz), 13.9, 12.0; ¹⁹F NMR (565 MHz, CDCl₃) δ : -99.0 (d, J ＝273.1 Hz), -99.5 (d, J ＝273.1 Hz); HRMS (ESI) calcd for C₁₇H₂₁BrF₂O₂SNa (M+Na)⁺ 429.0306, found 429.0320.

  3-苯硫基亚甲基-2, 2-二氟-6-溴十二酸乙酯(3ga): 63 mg, 黄色液体, 产率70%.¹H NMR (400 MHz, CDCl₃) δ : 7.35~7.32 (m, 4H), 7.31~7.28 (m, 1H), 6.61 (s, 1H), 4.33 (q, J ＝7.1 Hz, 2H), 4.08~4.02 (m, 1H), 2.68~2.61 (m, 1H), 2.52~2.44 (m, 1H), 2.09~1.76 (m, 4H), 1.57~1.41 (m, 2H), 1.35~1.26 (m, 7H), 0.90 (t, J ＝6.8 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝34.6 Hz), 135.0, 131.2 (t, J ＝5.9 Hz), 130.9 (t, J ＝23.5 Hz), 129.9, 129.3, 127.5, 113.6 (t, J ＝251.6 Hz), 63.2, 57.4, 39.2, 37.7, 31.2 (t, J ＝3.3 Hz), 31.2, 27.2, 22.5, 14.0, 13.9; ¹⁹F NMR (565 MHz, CDCl₃)δ : -99.0 (d, J ＝273.1 Hz), -99.5 (d, J ＝273.3 Hz); HRMS (ESI) calcd for C₂₀H₂₇BrF₂O₂SNa (M+Na)⁺ 471.0775, found 471.0791.

  3-苯硫基亚甲基-8-叔丁基二甲基硅氧基-2, 2-二氟-6-溴辛酸乙酯(3ha): 60 mg, 黄色液体, 产率56%.¹H NMR (400 MHz, CDCl₃) δ : 7.35~7.34 (m, 4H), 7.31~7.28 (m, 1H), 6.60 (s, 1H), 4.33 (q, J ＝7.1 Hz, 2H), 4.27~4.20 (m, 1H), 3.81~3.78 (m, 2H), 2.69~2.61 (m, 1H), 2.53~2.45 (m, 1H), 2.10~1.95 (m, 4H), 1.33 (t, J ＝7.1 Hz, 3H), 0.89 (s, 9H), 0.06 (d, J ＝1.9 Hz, 6H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝34.7 Hz), 135.1, 131.2 (t, J ＝5.9 Hz), 130.7 (t, J ＝23.4 Hz), 130.0, 129.3, 127.6, 113.6 (t, J ＝252.0 Hz), 63.2, 60.6, 53.7, 41.9, 38.1, 31.1 (t, J ＝3.5 Hz), 25.9, 18.3, 13.9, -5.4, -5.4; ¹⁹F NMR (565 MHz, CDCl₃) δ : -99.1 (d, J ＝272.6 Hz), -99.7 (d, J ＝272.3 Hz); HRMS (ESI) calcd for C₂₃H₃₅BrF₂O₃SSiNa (M+Na)⁺ 559.1120, found 559.1129.

  3-苯硫基亚甲基-8-乙酰氧基-2, 2-二氟-6-溴辛酸乙酯(3ia): 45 mg, 黄色液体, 产率48%.¹H NMR (600 MHz, CDCl₃) δ : 7.35 (d, J ＝4.3 Hz, 4H), 7.32~7.28 (m, 1H), 6.62 (s, 1H), 4.35~4.29 (m, 3H), 4.25~4.21 (m, 1H), 4.16~4.12 (m, 1H), 2.69~2.64 (m, 1H), 2.53~2.48 (m, 1H), 2.20~2.09 (m, 3H), 2.05 (s, 3H), 2.03~1.97 (m, 1H), 1.33 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 170.9, 163.4 (t, J ＝34.7 Hz), 134.9, 131.6 (t, J ＝5.8 Hz), 130.5 (t, J ＝23.4 Hz), 123.0, 129.3, 127.6, 113.6 (t, J ＝252.2 Hz), 63.2, 62.2, 52.3, 37.8, 37.8, 31.1 (t, J ＝3.4 Hz), 20.9, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -98.8 (d, J ＝273.5 Hz), -99.7 (d, J ＝273.4 Hz); HRMS (ESI) calcd for C₁₉H₂₃BrF₂O₄SNa (M+Na)⁺ 487.0361, found 487.0366.

  3-苯硫基亚甲基-2, 2-二氟-6, 8-二溴辛酸乙酯(3ja): 62 mg, 黄色液体, 产率64%.¹H NMR (600 MHz, CDCl₃) δ : 7.37~7.34 (m, 4H), 7.32~7.29 (m, 1H), 6.63 (s, 1H), 4.35 (q, J ＝7.1 Hz, 2H), 4.28~4.23 (m, 1H), 3.64~3.61 (m, 2H), 2.69~2.65 (m, 1H), 2.39~2.26 (m, 2H), 2.12~2.00 (m, 2H), 1.34 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝34.6 Hz), 134.8, 131.7 (t, J ＝5.9 Hz), 130.6 (t, J ＝11.7 Hz), 130.1, 129.3, 127.6, 113.5 (t, J ＝251.4 Hz), 63.3, 54.0, 41.3, 37.5, 31.1, 31.0 (t, J ＝3.4 Hz), 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ :-98.5 (d, J ＝273.4 Hz), -99.8 (d, J ＝273.3 Hz); HRMS (ESI) calcd for C₁₇H₂₀Br₂F₂O₂SNa (M+Na)⁺ 506.9411, found 506.9413.

  3-苯硫基亚甲基-2, 2-二氟-8-氯-6-溴辛酸乙酯(3ka): 48 mg, 黄色液体, 产率55%.¹H NMR (400 MHz, CDCl₃) δ : 7.38~7.30 (m, 5H), 6.64 (s, 1H), 4.36 (q, J ＝7.1 Hz, 2H), 4.22~4.26 (m, 1H), 3.84~3.74 (m, 2H), 2.72~2.65 (m, 1H), 2.58~2.50 (m, 1H), 2.34~2.19 (m, 2H), 2.15~1.99 (m, 2H), 1.35 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝34.6 Hz), 134.9, 131.7 (t, J ＝5.9 Hz), 130.6 (t, J ＝23.9 Hz), 130.1, 129.3, 127.6, 113.5 (t, J ＝252.6 Hz), 63.3, 52.8, 42.7, 41.3, 37.6, 31.0 (t, J ＝3.6 Hz), 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ :-98.5 (d, J ＝273.6 Hz), -99.9 (d, J ＝273.5 Hz); HRMS (ESI) calcd for C₁₇H₂₀BrClF₂O₂SNa (M+Na)⁺ 462.9916, found 462.9921.

  3-苯硫基亚甲基-8-邻苯二甲酰胺基-2, 2-二氟-6-溴辛酸乙酯(3la): 56 mg, 黄色液体, 产率51%.¹H NMR (600 MHz, CDCl₃) δ : 7.85~7.82 (m, 2H), 7.73~7.70 (m, 2H), 7.38~7.33 (m, 4H), 7.31~7.29 (m, 1H), 6.61 (s, 1H), 4.27~4.22 (m, 2H), 4.08~4.05 (m, 1H), 3.96~3.87 (m, 2H), 2.67~2.63 (m, 1H), 2.52~2.47 (m, 1H), 2.31~2.19 (m, 2H), 2.11~1.98 (m, 2H), 1.29 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 168.2, 163.4 (t, J ＝34.6 Hz), 134.9, 134.0, 132.0, 131.6 (t, J ＝5.7 Hz), 130.5 (t, J ＝23.1 Hz), 130.0, 129.3, 127.6, 123.3, 113.5 (t, J ＝252.2 Hz), 63.1, 52.8, 37.7, 37.6, 36.4, 31.0 (t, J ＝3.3 Hz), 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -98.2 (d, J ＝274.0 Hz), -100.2 (d, J ＝274.0 Hz); HRMS (ESI) calcd for C₂₅H₂₄- BrF₂NO₄SNa (M+Na)⁺ 574.0470, found 574.0469.

  3-甲硫基亚甲基-8-甲氧基-2, 2-二氟-6-溴辛酸乙酯(3ma): 46 mg, 黄色液体, 产率62%.¹H NMR (600 MHz, CDCl₃) δ : 6.33 (s, 1H), 4.34 (q, J ＝7.1 Hz, 2H), 4.18~4.14 (m, 1H), 3.58~3.51 (m, 2H), 3.34 (s, 3H), 2.57~2.52 (m, 1H), 2.40~2.35 (m, 1H), 2.29 (s, 3H), 2.12~2.07 (m, 1H), 2.05~2.00 (m, 2H), 1.97~1.91 (m, 1H), 1.35 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝35.0 Hz), 134.6 (t, J ＝5.8 Hz), 127.5 (t, J ＝23.6 Hz), 113.8 (t, J ＝252.1 Hz), 70.1, 63.0, 58.8, 53.7, 39.1, 38.3, 31.1 (t, J ＝3.5 Hz), 18.4, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -100.8; HRMS (ESI) calcd for C₁₃H₂₁- BrF₂O₃SNa (M+Na)⁺ 397.0255, found 397.0258.

  3-甲硫基亚甲基-4-(2'-溴环己基)-2, 2-二氟丁酸乙酯(3na): 62 mg, 黄色液体, 产率84%, dr 1.8:1. ¹H NMR (400 MHz, CDCl₃) of major isomer δ : 6.48 (s, 1H), 4.56 (s, 1H), 4.34 (q, J ＝7.1 Hz, 2H), 2.30 (s, 3H), 2.24 (m, 1H), 2.17 (d, J ＝13.9 Hz, 1H), 1.87~1.78 (m, 2H), 1.77~1.73 (m, 1H), 1.58~1.52 (m, 2H), 1.48~1.44 (m, 1H), 1.35 (t, J ＝7.1 Hz, 3H), 1.33~1.28 (m, 1H), 1.27~1.25 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) of major isomer δ : 163.5 (t, J ＝35.1 Hz), 135.8 (t, J ＝6.3 Hz), 125.9 (t, J ＝23.6 Hz), 113.8 (t, J ＝251.8 Hz), 63.0, 61.7, 40.8, 39.1, 35.0, 27.0, 25.5, 20.8, 18.3, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) of major isomer δ : -99.8 (d, J ＝268.8 Hz), -100.5 (d, J ＝268.8 Hz); HRMS (ESI) calcd for C₁₄H₂₁BrF₂O₂SNa (M+Na)⁺ 393.0306, found 393.0304.

  3-甲硫基亚甲基-4-甲氧基-2, 2-二氟-6-溴辛酸乙酯(3oa): 47 mg, 黄色液体, 产率63%, dr 1.5:1. ¹H NMR (400 MHz, CDCl₃) of major isomer δ : 6.62 (s, 1H), 4.39~4.32 (m, 2H), 4.28~4.22 (m, 1H), 4.18 (d, J ＝9.7 Hz 1H), 3.30 (s, 3H), 2.37 (s, 3H), 2.27~2.16 (m, 1H), 2.07~1.79 (m, 3H), 1.37 (t, J ＝7.2 Hz, 3H), 1.06 (t, J ＝7.2 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) of major isomer δ : 163.1 (t, J ＝34.9 Hz), 136.2 (t, J ＝5.5 Hz), 127.1 (t, J ＝22.7 Hz), 113.6 (t, J ＝252.3 Hz), 78.7 (t, J ＝3.6 Hz), 57.0, 56.6, 46.2, 32.6, 18.7, 13.9, 11.9; ¹⁹F NMR (565 MHz, CDCl₃) of major isomer δ : -99.4 (d, J ＝270.2 Hz), -103.18 (d, J ＝270.1 Hz); HRMS (ESI) calcd for C₁₃H₂₁BrF₂O₃SNa (M+Na)⁺ 397.0255, found 397.0268.

  6-甲基-3-甲硫基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3pa): 38 mg, 黄色液体, 产率55%. ¹H NMR (400 MHz, CDCl₃) δ : 6.30 (s, 1H), 4.35 (q, J ＝7.1 Hz, 2H), 2.49~2.45 (m, 2H), 2.30 (s, 3H), 1.97~1.93 (m, 2H), 1.77 (s, 6H), 1.36 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝35.2 Hz), 133.9 (t, J ＝5.7 Hz), 128.3 (t, J ＝23.2 Hz), 113.9 (t, J ＝252.2 Hz), 66.9, 63.0, 46.7, 34.1, 30.0 (t, J ＝3.7 Hz), 18.4, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -100.9; HRMS (ESI) calcd for C₁₂H₁₉BrF₂-O₂SNa (M+Na)⁺ 367.0149, found 367.0145.

  5, 5-二甲基-3-苯硫基亚甲基-2, 2-二氟-6-溴己酸乙酯(3qa): 30 mg, 黄色液体, 产率37%;¹H NMR (400 MHz, CDCl₃) δ : 7.37~7.28 (m, 5H), 6.72 (s, 1H), 4.31 (q, J ＝7.1 Hz, 2H), 3.36 (s, 2H), 2.45 (s, 2H), 1.31 (t, J ＝7.1 Hz, 3H), 1.08 (s, 6H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.6 (t, J ＝35.2 Hz), 134.7, 133.6 (t, J ＝6.6 Hz), 130.4, 129.7, 129.3, 127.5, 113.0 (t, J ＝251.6 Hz), 63.1, 46.1, 40.5 (t, J ＝2.3 Hz), 36.2, 25.9, 13.9; ¹⁹F NMR (565 MHz, CDCl₃)δ : -96.1; HRMS (ESI) calcd for C₁₇H₂₁BrF₂- O₂SNa (M+Na)⁺ 429.0306, found 429.0310.

  6-苯基-3-甲硫基亚甲基-2, 2-二氟-6-溴己酸乙酯(3ra): 49 mg, 黄色液体, 产率62%.¹H NMR (400 MHz, CDCl₃) δ : 7.41~7.39 (m, 2H), 7.37~7.33 (m, 2H), 7.32~7.28 (m, 1H), 6.31 (s, 1H), 5.00~4.95 (m, 1H), 4.33 (q, J ＝7.1 Hz, 2H), 2.51~2.33 (m, 4H), 2.30 (s, 3H), 1.34 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝35.0 Hz), 141.6, 134.9 (t, J ＝5.9 Hz), 128.8, 128.5, 127.3, 127.0 (t, J ＝23.9 Hz), 113.7 (t, J ＝252.4 Hz), 63.1, 54.5, 38.5, 31.7 (t, J ＝3.4 Hz), 18.4, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -100.5 (d, J ＝269.6 Hz), -101.0 (d, J ＝269.7 Hz); HRMS (ESI) calcd for C₁₆H₁₉BrF₂O₂SNa (M+Na)⁺ 415.0149, found 415.0150.

  7-苯基-3-甲硫基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3sa): 40 mg, 黄色液体, 产率50%.¹H NMR (600 MHz, CDCl₃) δ : 7.34~7.28 (m, 3H), 7.24~7.21 (m, 2H), 6.29 (s, 1H), 4.33 (q, J ＝7.1 Hz, 1H), 4.22~4.17 (m, 1H), 3.24~3.14 (m, 1H), 2.62~2.55 (m, 1H), 2.45~2.35 (m, 1H), 2.28 (s, 3H), 2.11~2.02 (m, 1H), 1.95~1.86 (m, 1H), 1.35 (t, J ＝7.2 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝34.7 Hz), 138.1, 134.7 (t, J ＝5.7 Hz), 129.2, 128.4, 127.2 (t, J ＝23.6 Hz), 126.9, 113.8 (t, J ＝252.3 Hz), 63.0, 56.5, 45.6, 37.1, 31.0 (t, J ＝3.4 Hz), 18.4, 13.9; ¹⁹F NMR (565 MHz, CDCl₃) δ : -100.5 (d, J ＝268.7 Hz), -101.1 (d, J ＝268.7 Hz); HRMS (ESI) calcd for C₁₇H₂₁BrF₂O₂SNa (M+Na)⁺ 429.0306, found 429.0309.

  3-甲硒基亚甲基-2, 2-二氟-6-溴庚酸乙酯(3ta): 28 mg, 黄色液体, 产率37%.¹H NMR (400 MHz, CDCl₃) δ : 6.68 (s, 1H), 4.35 (q, J ＝7.1 Hz, 2H), 4.15~4.07 (m, 1H), 2.53~2.46 (m, 1H), 2.41~2.33 (m, 1H), 2.18 (s, 3H), 2.02~1.87 (m, 2H), 1.73 (d, J ＝6.7 Hz, 3H), 1.36 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.2 (t, J ＝35.2 Hz), 130.1 (t, J ＝23.0 Hz), 129.5 (t, J ＝5.8 Hz), 114.4 (t, J ＝253.2 Hz), 63.2, 50.7, 39.7, 32.1 (t, J ＝3.4 Hz), 26.5, 14.0, 8.6; ¹⁹F NMR (565 MHz, CDCl₃) δ : -101.7 (d, J ＝262.5 Hz), -102.2 (d, J ＝262.5 Hz); HRMS (ESI) calcd for C₁₁H₁₇F₂O₂SeNa (M+Na)⁺ 400.9437, found 400.9438.

  3-苯硫基亚甲基-1-对甲苯磺酰哌嗪基-2, 2-二氟-6-溴庚酮(3ab): 83 mg, 黄色液体, 产率71%.¹H NMR (600 MHz, CDCl₃) δ : 7.63 (d, J ＝8.2 Hz, 1H), 7.37~7.31 (m, 3H), 6.55 (s, 1H), 4.11~4.09 (m, 1H), 3.80~3.68 (m, 4H), 3.07~3.05 (m, 4H), 2.46~2.41 (m, 4H), 2.34~2.29 (m, 1H), 1.97~1.84 (m, 2H), 1.70 (d, J ＝6.7 Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ : 161.2 (t, J ＝30.9 Hz), 144.2, 134.9 (t, J ＝2.4 Hz), 132.1, 131.8 (t, J ＝4.9 Hz), 130.5, 129.9, 129.4, 127.9, 127.7, 116.3 (t, J ＝253.7 Hz), 50.6, 46.0, 45.7, 45.3, 42.6, 39.6, 31.3 (t, J ＝3.0 Hz), 26.4, 21.6; ¹⁹F NMR (565 MHz, CDCl3) δ : -93.6 (d, J ＝279.0 Hz), -94.1 (d, J ＝278.9 Hz); HRMS (ESI) calcd for C₂₅H₂₉Br- F₂N₂O₃S₂Na (M+Na)⁺ 609.0663, found 609.0657.

  3-苯硫基亚甲基-1-叔丁氧羰基哌嗪基-2, 2-二氟-6-溴庚酮(3ac): 79 mg, 黄色液体, 产率74%.¹H NMR (600 MHz, CDCl₃) δ : 7.40 (d, J ＝7.3 Hz, 2H), 7.36 (t, J ＝7.5 Hz, 2H), 7.33~7.30 (m, 1H), 6.60 (s, 1H), 4.18~4.12 (m, 1H), 3.63 (d, J ＝32.8 Hz, 4H), 3.49 (d, J ＝4.5 Hz, 4H), 2.54~2.50 (m, 1H), 2.42~2.37 (m, 1H), 2.00~1.99 (m, 1H), 1.94~1.92 (m, 1H), 1.73 (d, J ＝6.6 Hz, 3H), 1.47 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ : 161.3 (t, J ＝31.6 Hz), 154.4, 135.2, 131.6 (t, J ＝5.7 Hz), 130.5, 129.4, 128.4 (t, J ＝22.9 Hz), 127.8, 118.2 (t, J ＝253.1 Hz), 80.5, 50.7, 45.7, 43.2, 39.7, 31.5 (t, J ＝3.0 Hz), 28.3, 26.5; ¹⁹F NMR (565 MHz, CDCl₃) δ : -94.0; HRMS (ESI) calcd for C₂₃H₃₁BrF₂N₂O₃SNa (M+Na)⁺ 555.1099, found 555.1095.

  3-苯硫基亚甲基-1-吗啉基-2, 2-二氟-6-溴庚酮(3ad): 53 mg, 黄色液体, 产率61%.¹H NMR (600 MHz, CDCl₃) δ : 7.40 (d, J ＝7.4 Hz, 2H), 7.36 (t, J ＝7.5 Hz, 2H), 7.31 (t, J ＝7.2 Hz, 1H), 6.60 (s, 1H), 4.20~4.13 (m, 1H), 3.75~3.65 (m, 8H), 2.55~2.50 (m, 1H), 2.43~2.37 (m, 1H), 2.04~1.98 (m, 1H), 1.96~1.90 (m, 1H), 1.73 (d, J ＝6.6 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 161.2 (t, J ＝30.4 Hz), 135.2 (t, J ＝1.9 Hz), 131.6 (t, J ＝5.1 Hz), 130.4, 129.4, 127.8, 116.4 (t, J ＝253.3 Hz), 66.7, 66.5, 50.7, 46.5, 43.5, 39.7, 31.5 (t, J ＝3.4 Hz), 26.5; ¹⁹F NMR (565 MHz, CDCl₃) δ : -93.8 (d, J ＝278.2 Hz), -94.3 (d, J ＝278.2 Hz); HRMS (ESI) calcd for C₁₈H₂₂BrF₂NO₂SNa (M+ Na)⁺ 456.0415, found 456.0411.

  3-苯硫基亚甲基-2, 2-二氟-6-溴-N, N -二乙基庚酰胺(3ae): 36 mg, 黄色液体, 产率43%.¹H NMR (400 MHz, CDCl₃) δ : 7.41 (d, J ＝7.4 Hz, 2H), 7.35 (t, J ＝7.4 Hz, 2H), 7.30 (d, J ＝7.0 Hz, 1H), 6.57 (s, 1H), 4.21~4.13 (m, 1H), 3.49~3.40 (m, 4H), 2.53~2.46 (m, 1H), 2.42~2.32 (m, 1H), 2.06~1.89 (m, 2H), 1.73 (d, J ＝6.6 Hz, 3H), 1.24 (t, J ＝6.9 Hz, 3H), 1.17 (t, J ＝7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 161.9 (t, J ＝30.3 Hz), 135.6 (t, J ＝2.5 Hz), 130.9 (t, J ＝4.7 Hz), 130.5, 129.3, 129.2 (t, J ＝22.6 Hz), 116.7 (t, J ＝254.1 Hz), 50.9, 41.9 (t, J ＝4.1 Hz), 41.7, 39.7, 31.6 (t, J ＝3.3 Hz), 26.5, 14.1, 12.3; ¹⁹F NMR (565 MHz, CDCl₃) δ : -93.6 (d, J ＝274.4 Hz), -94.6 (d, J ＝274.4 Hz); HRMS (ESI) calcd for C₁₈H₂₄BrF₂NOSNa (M+Na)⁺ 442.0622, found 442.0619.

  3-苯硫基亚甲基-2, 2-二氟-6-溴-N -苄基庚酰胺(3af): 59 mg, 黄色液体, 产率54%.¹H NMR (400 MHz, CDCl₃) δ : 7.39~7.32 (m, 5H), 7.31~7.26 (m, 5H), 6.93 (s, 1H), 6.60 (s, 1H), 4.55 (dd, J ＝5.5, 3.6 Hz, 2H), 4.22~4.13 (m, 1H), 2.70~2.63 (m, 1H), 2.55~2.48 (m, 1H), 2.13~2.05 (m, 1H), 2.01~1.91 (m, 1H), 1.76 (d, J ＝6.6 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 163.4 (t, J ＝30.9 Hz), 136.8 134.8, 131.1 (t, J ＝23.3 Hz), 130.6 (t, J ＝5.3 Hz), 130.3, 129.4, 128.8, 127.9, 127.9, 127.7, 115.4 (t, J ＝255.6 Hz), 50.9, 43.8, 39.5, 31.8 (t, J ＝3.5 Hz), 26.5; ¹⁹F NMR (565 MHz, CDCl₃) δ : -98.9 (d, J ＝260.6 Hz), -100.2 (d, J ＝260.6 Hz); HRMS (ESI) calcd for C₂₁H₂₂BrF₂NOSNa (M+Na)⁺ 476.0466, found 476.0463.

  3-苯硫基亚甲基-2, 2-二氟-6-溴庚酸甲酯(3ag): 57 mg, 黄色液体, 产率75%.¹H NMR (600 MHz, CDCl₃) δ : 7.39~7.36 (m, 4H), 7.34~7.30 (m, 1H), 6.64 (s, 1H), 4.20~4.14 (m, 1H), 3.90 (s, 3H), 2.65~2.60 (m, 1H), 2.51~2.46 (m, 1H), 2.06~1.95 (m, 2H), 1.77 (dd, J ＝6.6, 0.5 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 164.0 (t, J ＝34.8 Hz), 134.9, 131.5 (t, J ＝5.9 Hz), 130.6 (t, J ＝23.5 Hz), 130.1, 129.3, 127.7, 113.6 (t, J ＝251.7 Hz), 53.7, 50.5, 39.7, 31.4 (t, J ＝3.4 Hz), 26.5; ¹⁹F NMR (565 MHz, CDCl₃) δ : -99.2; HRMS (ESI) calcd for C₁₅H₁₇BrF₂- O₂SNa (M+Na)⁺ 400.9993, found 400.9989.

  2-三氟甲基-1-苯硫基-5-溴己烯(3ah): 28 mg, 黄色液体, 产率42%.¹H NMR (600 MHz, CDCl₃) δ : 7.45 (d, J ＝7.4 Hz, 2H), 7.38 (t, J ＝7.4 Hz, 2H), 7.34 (t, J ＝7.3 Hz, 1H), 6.68 (s, 1H), 4.16~4.07 (m, 1H), 2.61~2.48 (m, 1H), 2.47~2.29 (m, 1H), 2.03~1.88 (m, 2H), 1.74 (d, J ＝6.7 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 134.9 (q, J ＝3.1 Hz), 130.9, 129.5, 128.1, 127.15 (q, J ＝574.5 Hz), 123.51 (q, J ＝29.7 Hz), 50.1, 39.5, 31.1 (q, J ＝1.8 Hz), 26.5; ¹⁹F NMR (565 MHz, CDCl₃) δ : -61.5; MS (EI) m /z (%): 340 (M⁺, ⁸¹Br, 1), 338 (M⁺, ⁷⁹Br, 24), 258 (24), 217 (100), 189 (3), 184 (62).

  2-三氟甲基-1-苯硫基-5-碘己烯(3ai): 23 mg, 黄色液体, 产率30%.¹H NMR (600 MHz, CDCl₃) δ : 7.48 (d, J ＝7.2 Hz, 2H), 7.40 (t, J ＝7.4 Hz, 2H), 7.37 (d, J ＝7.2 Hz, 1H), 6.72 (s, 1H), 4.35~4.01 (m, 1H), 2.75~2.50 (m, 1H), 2.42~2.27 (m, 1H), 1.98 (d, J ＝6.8 Hz, 3H), 1.94 (dd, J ＝9.6, 4.8 Hz, 1H), 1.83~1.71 (m, 1H); ¹³C NMR (151 MHz, CDCl₃) δ : 134.90 (q, J ＝3.0 Hz), 131.0, 129.4, 128.1, 123.57 (q, J ＝185.5 Hz), 123.35 (q, J ＝30.0 Hz), 41.1, 33.1, 28.9, 28.5; ¹⁹F NMR (565 MHz, CDCl₃)δ : -61.5; MS (EI) m /z (%): 386 (M⁺, 18), 259 (29), 217 (100), 189 (1), 184 (49).

  1-苯硫基-2-对甲苯磺酰基-5-氯己烯(3aj): 43 mg, 黄色液体, 产率57%.¹H NMR (600 MHz, CDCl₃) δ : 7.92 (d, J ＝8.1 Hz, 2H), 7.45 (d, J ＝7.1 Hz, 2H), 7.36 (dd, J ＝9.8, 5.9 Hz, 5H), 7.02 (s, 1H), 3.93~3.99 (m, 1H), 2.58~2.50 (m, 1H), 2.45 (s, 3H), 2.44~2.37 (m, 1H), 2.02~2.08 (m, 1H), 1.76~1.82 (m, 1H), 1.47 (d, J ＝6.5 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ : 144.8, 142.6, 137.6, 135.7, 132.6, 131.1, 129.9, 129.5, 128.5, 127.5, 57.5, 39.4, 30.5, 25.4, 21.7; HRMS (ESI) calcd for C₁₉H₂₁ClO₂S₂Na (M+Na)⁺ 403.0564, found 403.0568.

  辅助材料(Supporting Information)  化合物3的¹H NMR、¹³C NMR和¹⁹F NMR谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载

  
  
• 1. [1]

     For selected reviews, see: (a) Purser, S.; Moore, P. R. Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
     (b) O'Hagan, D. Chem. Soc. Rev. 2008, 37, 308.

  2. [2]

     (a) Burke, T. R.; Lee, K. Acc. Chem. Res. 2003, 36, 426.
     (b) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
     (c) An, L.; Tong, F.; Zhang, X. Acta Chim. Sinica 2018, 76, 977(in Chinese).
     (安伦, 童非非, 张新刚, 化学学报, 2018, 76, 977.)
     (d) Tao, X.; Sheng, R.; Bao, K.; Wang, Y.; Jin, Y. Chin. J. Org. Chem. 2019, 39, 2726(in Chinese).
     (陶雪芬, 盛荣, 鲍堃, 王玉新, 金银秀, 有机化学, 2019, 39, 2726.)
     (e) Dai, J.; Lei, W.; Liu, Q. Acta Chim. Sinica 2019, 77, 911(in Chinese).
     (戴建玲, 雷文龙, 刘强, 化学学报, 2019, 77, 911.)

  3. [3]

     (a) Long, Z.-Y.; Chen, Q.-Y. J. Org. Chem. 1999, 64, 4775.
     (b) Huang, X.-T.; Chen, Q.-Y. J. Org. Chem. 2001, 66, 4651.
     (c) Ke, M.; Feng, Q.; Yang, K.; Song, Q. Org. Chem. Front. 2016, 3, 150.
     (d) Feng, X.; Wang, X.; Chen, H.; Tang, X.; Guo, M.; Zhao, W.; Wang, G. Org. Biomol. Chem. 2018, 16, 2841.
     (e) Li, K.-K.; Zhang, X.-X.; Chen, J.-C.; Gang, Y.; Yang, C.-H.; Zhang, K.-Y.; Zhou, Y.-Y.; Fan, B.-M. Org. Lett. 2019, 21, 9914.

  4. [4]

     (a) He, Y.-T.; Wang, Q.; Li, L.-H.; Liu, X.-Y.; Xu, P.-F.; Liang, Y.-M. Org. Lett. 2015, 17, 5188.
     (b) He, Y.-T.; Li, L.-H.; Wang, Q.; Wu, W.; Liang, Y.-M. Org. Lett. 2016, 18, 5158.
     (c) Wang, Q.; Zheng, L.; He, Y.-T.; Liang, Y.-M. Chem. Commun. 2017, 53, 2814.
     (d) Zhang, Y.; Zhang, J.; Hu, B.; Ji, M.; Ye, S.; Zhu, G. Org. Lett. 2018, 20, 2988.
     (e) Liang, J.-Q.; Huang, G.-Z; Peng, P.; Zhang, T.-Y.; Wu, J.-J.; Wu, F.-H. Adv. Synth. Catal. 2018, 360, 2221.

  5. [5]

     Zhang, B.-S.; Gao, L.-Y.; Zhang, Z.; Wen, Y.-H.; Liang, Y.-M. Chem. Commun. 2018, 54, 1185. doi: 10.1039/C7CC09083H

  6. [6]

     Xiang, Y.; Li, Y.; Kuang, Y.; Wu, J. Chem.-Eur. J. 2017, 23, 1032. doi: 10.1002/chem.201605336

  7. [7]

     (a) Wang, S.; Zhang, J.; Kong, L.; Tan, Z.; Bai, Y.; Zhu, G. Org. Lett. 2018, 20, 5631.
     (b) Guo, W.-H.; Zhao, H.-Y.; Luo, Z.-J.; Zhang, S.; Zhang, X. ACS Catal. 2019, 9, 38.

  8. [8]

     Li, Y.; Li, H.; Hu, J. Tetrahedron 2009, 65, 478. doi: 10.1016/j.tet.2008.11.011

  9. [9]

     Xu, T.; Cheung, C. W.; Hu, X. Angew. Chem., Int. Ed. 2014, 53, 4910. doi: 10.1002/anie.201402511

  10. [10]

      Zhong, J.-J.; Yang, C.; Chang, X.-Y.; Zou, C.; Lu, W.; Che, C.-M. Chem. Commun. 2017, 53, 8948. doi: 10.1039/C7CC03823B

  11. [11]

      Li, G.; Cao, Y.-X.; Luo, C.-G.; Su, Y.-M.; Li, Y.; Lan, Q.; Wang, X.-S. Org. Lett. 2016, 18, 4806. doi: 10.1021/acs.orglett.6b02216

  12. [12]

      Wu, G.; von Wangelin, A. J. V. Chem. Sci. 2018, 9, 1795. doi: 10.1039/C7SC04916A

  13. [13]

      Shang, T.; Zhang, J.; Zhang, Y.; Zhang, F.; Li, X.-S.; Zhu, G. Org. Lett. 2020, 22, 3667. doi: 10.1021/acs.orglett.0c01163

  14. [14]

      Xiong, Z.; Zhang, F.; Yu, Y.; Tan, Z.; Zhu, G. Org. Lett. 2020, 22, 4088. doi: 10.1021/acs.orglett.0c01147

  15. [15]

      For selected reviews on photocatalysis, see: (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102.
      (b) Xuan, J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51, 6828.
      (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
      (d) Matsui, J. K.; Lang, S. B.; Heitz, D. R.; Molander, G. A. ACS Catal. 2017, 7, 2563.

  16. [16]

      For selected reports on remote C-H halogention, see: (a) Kundu, R.; Ball, Z. T. Org. Lett. 2010, 12, 2460.
      (b) Liu, T.; Myers, M. C.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 306.
      (c) Herron, A. N.; Liu, D.; Xia, G.; Yu, J.-Q. J. Am. Chem. Soc. 2020, 142, 2766.
      (d) Short, M. A.; Blackburn, J. M.; Roizen, J. L. Angew. Chem., Int. Ed. 2018, 57, 296.

  17. [17]

      (a) Yang, Z.; Chen, X.; Kong, W.; Xia, S.; Zheng, R.; Luo, F.; Zhu, G. Org. Biomol. Chem. 2013, 11, 2175.
      (b) Zhu, G.; Kong, W.; Feng, H.; Qian, Z. J. Org. Chem. 2014, 79, 1786.

  18. [18]

      Nie, X.; Cheng, C.; Zhu, G. Angew. Chem., Int. Ed. 2017, 56, 1898. doi: 10.1002/anie.201611697

  19. [19]

      (a) Jin, W.; Wu, M.; Xiong, Z.; Zhu, G. Chem. Commun. 2018, 54, 7924.
      (b) Wan, Y.; Shang, T.; Lu, Z.; Zhu, G. Org. Lett. 2019, 21, 4187.

  20. [20]

      For selected reports on HAT of vinyl radicals, see: (a) Curran, D. P.; Shen, W. J. Am. Chem. Soc. 1993, 115, 6051.
      (b) Bogen, S.; Malacria, M. J. Am. Chem. Soc. 1996, 118, 3992.
      (c) Hu, M.; Fan, J.-H.; Liu, Y.; Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed. 2015, 54, 9577.
      (d) Qiu, J.-K.; Jiang, B.; Zhu, Y.-L.; Hao, W.-J.; Wang, D.-C.; Sun, J.; Wei, P.; Tu, S.-J.; Li, G. J. Am. Chem. Soc. 2015, 137, 8928.
      (e) Huang, L.; Ye, L.; Li, X.-H.; Li, Z.-L.; Lin, J.-S.; Liu, X.-Y. Org. Lett. 2016, 18, 5284.
      (f) Gloor, C. S.; Dénès, F.; Renaud, P. Angew. Chem., Int. Ed. 2017, 56, 13329.
      (g) An, X.-D.; Jiao, Y.-Y.; Zhang, H.; Gao, Y.; Yu, S. Org. Lett. 2018, 20, 401.
      (h) Ratushnyy, M.; Parasram, M.; Wang, Y.; Gevorgyan, V. Angew. Chem., Int. Ed. 2018, 57, 2712.
      (i) Wu, S.; Wu, X.; Wang, D.; Zhu, C. Angew. Chem., Int. Ed. 2019, 58, 1499.
      (j) Yang, S.; Wu, X.; Wu, S.; Zhu, C. Org. Lett. 2019, 21, 4837.
      (k) Liu, T.; Qu, C.; Xie, J.; Zhu, C. Chin. J. Org. Chem. 2019, 39, 1613(in Chinese).
      (刘涛, 屈川华, 谢劲, 朱成建, 有机化学, 2019, 39, 1613.)
      (l) Li, H.; Guo, L.; Feng, X.; Huo, L.; Zhu, S.; Chu, L. Chem. Sci. 2020, 11, 4904.
      (m) Wu, S.; Wu, X.; Wu, Z.; Zhu, C. Sci. China: Chem. 2019, 62, 1507.

• 

  图式 1  炔烃的卤-氟烷基化反应

  Scheme 1  Halo-fluoroalkylation of alkynes

  下载: 全尺寸图片 幻灯片
  

  图式 2  机理研究

  Scheme 2  Mechanistic studies

  下载: 全尺寸图片 幻灯片
  

  图 1  化合物1a和2a反应的开关灯实验

  Figure 1  Light on/off experiment of the reaction between 1a and 2a

  下载: 全尺寸图片 幻灯片
  

  图式 3  可能的反应机理

  Scheme 3  Possible reaction mechanism

  下载: 全尺寸图片 幻灯片

  表 1  炔硫醚远程溴-二氟烷基化反应条件优化^a

  Table 1.  Optimization of reaction conditions for the remote hlao-difluoroalkylation of thioalkynes

  Entry	Deviations from standard condition	Yieldb /% of 3aa/3aa'
  1	None	72/＜5
  2	Ru(bpy)3Cl2 instead of fac -Ir(ppy)3	25/5
  3	Et3N instead of 2, 6-lutidine	65/9
  4	Pyridine instead of 2, 6-lutidine	61/7
  5	2, 4, 6-collidine instead of 2, 6-lutidine	55/4
  6	KOAc instead of 2, 6-lutidine	70/8
  7	K2CO3 instead of 2, 6-lutidine	62/4
  8	K2HPO4 instead of 2, 6-lutidine	68/6
  9	MeCN instead of EtBr	69/10
  10	DMSO instead of EtBr	70/7
  11	DCM instead of EtBr	69/15
  12	THF instead of EtBr	7/2
  13	Without 2, 6-lutidine	9/4
  14	Without fac -Ir(ppy)3	NR
  a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), fac -Ir(ppy)3 (2 mol%), 2, 6-lutidine (0.4 mmol), EtBr (2 mL), 25 ℃, 15 W blue LEDs, 36 h. b Isolated yield. NR＝No reaction.

  下载: 导出CSV

  表 2  杂原子取代炔烃的底物范围^a

  Table 2.  Substrate scope of heteroalkynes

  a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), fac -Ir(ppy)3 (2 mol%), 2, 6-lutidine (0.4 mmol), EtBr, blue LEDs, 25 ℃, 36 h; isolated yields are given. b dr ＝1.8:1. c dr ＝1.5:1. d Determined by GC-MS. e Similar with the reaction of 1p, 11% yield of hydrodifluoroalkylation product 3ra' and＜5% yield of remote desaturated product 3ra'' was observed by GC-MS. f 14% yield of hydrodifluoroalkylation product 3sa' was observed by GC-MS.

  下载: 导出CSV

  表 3  自由基前体范围^a

  Table 3.  Scope of radical precursors

  a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), fac -Ir(ppy)3 (2 mol%), 2, 6-lutidine (0.4 mmol), EtBr, blue LEDs, 25 ℃, 36 h; isolated yields are given. b Umemoto’s reagent (0.4 mmol), NaX (0.6 mmol), and ClCH2CH2Cl were used instead of 2a and EtBr.

  下载: 导出CSV
•